(Stroke. 1999;30:873-879.)
© 1999 American Heart Association, Inc.
Original Contributions |
Influence of Platelet-Activating Factor on Cerebral Microcirculation in Rats
Part 1. Systemic Application
From the Departments of Neurosurgery (E.U.) and Surgery (S.P.) and the Institute for Surgical Research (A.B.), Grosshadern University Hospital, Ludwig-Maximilians-University, Munich, and the Department of Neurosurgery (L.S.), University Hospital, Mannheim, Germany.
Correspondence and reprint requests to Eberhard Uhl, MD, Department of Neurosurgery, Klinikum Grosshadern, Marchioninistr 15, 81377 Munich, Germany. E-mail eberhard.uhl{at}nc.med.uni-muenchen.de
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Abstract |
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Background and Purpose—Platelet-activating factor (PAF) has been demonstrated to have a mediator function in shock, with some of its deleterious effects being attributed to its influence on microcirculation. Systemic PAF concentrations as found in shock could also compromise the cerebral microcirculation. Our purpose in the present study was to examine the influence of systemically applied PAF on microvascular perfusion and leukocyte-endothelium interactions in cerebral microvessels.
Methods—A closed cranial window technique was used for intravital fluorescence microscopy of the brain surface. PAF was infused in concentrations of 10-12, 10-9, and 10-6 mol/L into the carotid artery (5 mL/h for 20 min) of Sprague-Dawley rats (n=30). The selective PAF receptor antagonist WEB 2170BS (2 mg/kg body weight) was used to inhibit specific PAF effects.
Results—The number of leukocytes (cells/100 µm · min) rolling along or adhering at the venular endothelium increased following infusion of PAF 10-6 mol/L from 7.7±2.5 to 24.4±8.9 (P<0.05) and from 1.9±0.5 to 6.9±2.2 (P<0.05), respectively, within 2 hours. Mean arterial pressure decreased from 92±22 mm Hg to 49±17 mm Hg (P<0.05). The lower concentrations of PAF were less effective to decrease mean arterial pressure but also induced leukocyte-endothelium interactions. The intravenous administration of WEB 2170BS 15 min before the infusion of PAF 10-6 mol/L prevented both systemic hypotension and activation of leukocyte-endothelium interactions.
Conclusions—Increased systemic blood levels of PAF as found during shock can not only cause systemic arterial hypotension but also induce leukocyte-endothelium interactions in cerebral venules. The activation of leukocytes was found to be independent of PAF-induced arterial hypotension. The specificity of these results is confirmed by the findings that WEB 2170BS could inhibit the PAF-induced systemic hypotension as well as the activation of leukocytes.
Key Words: cerebral circulation • leukocytes • platelet activating factor • rats
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Introduction |
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Platelet-activating factor (PAF) is an endogenous phospholipid with potent mediator functions in a variety of allergic and inflammatory diseases as well as in trauma and shock.1 PAF seems also to be involved in the development of secondary brain damage after traumatic or ischemic brain injury.2 The exact mechanisms of its deleterious effects, however, are still not completely understood. Besides its well-known systemic hypotensive properties, PAF has been shown to elicit marked changes in the microcirculation of peripheral organs, eg, dilation and constriction of arterioles,3 extravasation and edema,4 and induction of leukocyte-endothelium interactions.5 Whether these effects following PAF administration can also be observed in cerebral microcirculation has not yet been shown. Because PAF is released in excessive quantities during shock, we hypothesized that cerebral microcirculation is directly affected by the mediator, leading to an impairment of the perfusion independent of its hypotensive action in the systemic circulation. Therefore, the objective of the current experiments was to quantitatively assess the influence of PAF injected into the carotid artery on the cerebral microvessels, focusing on the induction of leukocyte-endothelium interactions and the integrity of the blood-brain barrier (BBB), by means of intravital fluorescence microscopy.
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Materials and Methods |
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Animals
Thirty adult male barrier-bred Sprague Dawley rats (body weight, 300±26 g) were used in this study. The animals had free access to tap water and pellet food. The experiments were conducted according to institutional guidelines and were approved by the state government of Bavaria.
Surgical Preparation
Anesthesia was induced by pentobarbital 3.6% (10
mL/kg body weight intraperitoneally). The animals
were placed on a feedback-controlled heating pad (Effenberger). The
rectal temperature was continuously controlled and maintained at
37.4±0.2C°. Polyethylene catheters (PE-50, Portex) were inserted
into the left femoral artery and vein for continuous measurement of the
arterial blood pressure, blood sampling, and infusion of
anesthetics and fluorescence dyes. Another catheter was
inserted into the left external carotid artery with placement of the
tip at the bifurcation of the common carotid artery for retrograde
infusion of PAF or vehicle, respectively, into the internal carotid
artery. After tracheotomy the animals were intubated with a modified
16-gauge cannula (B. Braun). After immobilization with pancuronium
bromide (initial bolus of 1.2 mg/kg body weight followed by continuous
infusion of 1.2 mg/h), the rats were mechanically ventilated (Harvard
ventilator model 683; PaCO2, 36 to 40
mm Hg; PaO2, 100 to 120 mm Hg).
Anesthesia was continued by intravenous
-chloralose (Merck; bolus of 5 mg/kg body weight).
Arterial blood samples (0.1 mL) were obtained in 20-minute
intervals for measurement of arterial blood gases, pH, base
excess (BE), and hemoglobin (Hb) concentration (ABL 300, Radiometer
A/S). For assessment of systemic leukocyte counts and hematocrit (Hct)
(Coulter Counter T450), blood samples (300 µl) were taken immediately
after implantation of the catheters, before application (0
minutes), at the end of the application of PAF (20 minutes), and at the
termination of the experiment (120 minutes). In case of a negative
BE6 >10 mmol/L, the half dose of NaHCO3
as calculated according to the formula
HCO3- mmol=BExkg body weightx0.3 was
infused. This was the case in 2 animals treated with PAF
10-6 mol/L receiving a total volume of 0.6 mL of
NaHCO3 The arterial blood pressure (MAP),
intracranial pressure (ICP), and airway pressure (AWP) were
continuously monitored (Honeywell model 3260 recorder).
The skull was fixed in a stereotactic frame (Model 900, David Knopf Inc) for implantation of a closed cranial window over the left parietal hemisphere according to Kawamura et al,7 with minor modifications. After a midsagittal skin incision from forehead to neck, the calvaria was exposed and a rectangular 4x7-mm window was trephined over the left parietal hemisphere, leaving the tabula interna intact. Two polyethylene catheters (PE-50, Portex) were inserted into a wall of dental cement (Paladur, Heraeus Kulzer GmbH), which surrounded the window, serving as inflow and outflow for superfusion of the exposed brain surface with artificial cerebrospinal fluid (CSF)7 and monitoring of the ICP. The influx catheter was led through subcutaneous tissue at the back of the animals to adjust the superfusate to body temperature. A cover glass (Menzel) was attached onto the still-formable cement, creating a horizontal plane for placement of the final cover glass. After hardening of the cement, the glass was removed and a hole was drilled through the cement down to the tabula interna. Then a plexiglass funnel was attached to the skin above the window. A silicon reservoir was inserted into the funnel surrounding the trephination. The reservoir and the funnel were filled with paraffin oil, exerting a gentle pressure (3 to 5 mm Hg) at the brain surface to prevent herniation of the brain after opening of the dura following removal of the final bone layer. Upon reflection of the dura, the silicone reservoir was filled with mock CSF, forming a layer under the paraffin oil. A round cover glass (Menzel; diameter, 12 mm; thickness, 0.13 mm) was placed and sealed tightly onto the cement wall with butyl-2-cyanoacrylate (Histoacryl, B. Braun). By this technique, herniation of the brain through the craniotomy is prevented and an optimal visibility of the brain surface is provided for intravital microscopy. Superfusion of the brain with mock CSF was then started, and the reservoir and the funnel were removed. The outflow catheter was adjusted 10 cm above the window to maintain pressure (ICP) in the cranial window at 10 to 12 mm Hg.
Platelet-Activating Factor and WEB 2170BS
Platelet-activating factor (C-16 PAF,
1-O-hexadecyl-2-(R)acetyl-sn-glycero-3-phosphocholine;
molecular weight, 525.7 Da; Bachem AG) was dissolved in isotonic
saline containing endotoxin-free bovine serum albumin (0.5%
solution; Sigma). Albumin was added to prevent PAF from
adsorption at unphysiological surfaces.
Concentrations of 10-12, 10-9, and
10-6 mol/L PAF were used. Using an infusion rate of 5 mL/h
for 20 minutes, a total dose of 0.88 pg (10-12 mol/L; 44
fg/min), 0.88 ng (10-9 mol/L; 44 pg/min), or 0.88 µg
(10-6 mol/L; 44 ng/min) was administered, respectively.
Infusion of isotonic saline with bovine serum albumin (0.5%
solution) was used as control. Because of the tachyphylactic properties
of PAF, only 1 concentration was used in each individual animal.
For testing the specificity of the effects induced by PAF, the competitive receptor antagonist WEB 2170BS (Boehringer Ingelheim) was administered in additional experiments. The antagonist (2 mg/kg body weight) was dissolved in isotonic saline and injected intravenously 15 minutes before the infusion of PAF 10-6 mol/L. The latter concentration was found to elicit the strongest response of the microcirculatory parameters.
In 3 control and 3 treated animals, respectively, systemic PAF levels were analyzed with use of a commercially available [125I]PAF radioimmunoassay (DuPont de Nemours GmbH, NEN Division). For that purpose, blood samples were taken before application (0 minutes), at the end of the application of PAF (after 20 minutes of infusion), and at the termination of the experiment (120 minutes). Animals used for the radioimmunoassay were not subjected to intravital microscopy.
Intravital Fluorescence Microscopy
The animals were placed on a computer-controlled microscope
stage for repeated analysis of identical segments of cerebral
blood vessels over extended time periods. The intravital
fluorescence microscope (Leitz) was equipped with a 75-W xenon
lamp and a Ploemopak filter block for epi-illumination. Leukocytes were
stained in vivo before each measurement by intravenous
injection of 0.1 mL of 0.1% Rhodamine 6G (Sigma Chemical).
Leukocyte-endothelium interactions were observed by use
of a N2 filter block and a salt water immersion objective
(x25). The intravital microscopic images were recorded by an SIT
video camera (C2400, Hamamatsu Photonics). Offline analysis of
the videotapes was performed by frame-to-frame analysis with a
television monitor (Trinitron PVM-2130QM, Sony) at a total
magnification of x998. To test the integrity of the blood-brain
barrier at the end of the experiment (online), 0.5 mL of a 5%
Na+-fluorescein solution (Sigma) was injected
intravenously. For observation of the extravasation of the
fluorescent marker, an I2 filter (Leitz) and an
objective with a magnification x10 were used. After the injection of
the fluorescent marker, the preparation was observed in short
intervals for another 20 minutes.
Analysis of Microcirculatory Parameters
The analysis of the pial microcirculation included
measurements of the arteriolar and venular diameters (in
micrometers), the number of rolling and adherent leukocytes
in venules (cells per 100 micrometers per minute), the
velocity of freely moving leukocytes in venules (millimeters per
second), and the integrity of the BBB (yes/no). Diameters were measured
with a computer-assisted microcirculation analysis system
(CAMAS).8 The white blood cells were classified according
to their interaction with the venular endothelium as
adherent, rolling, or freely moving leukocytes. Rolling leukocytes were
defined as cells having multiple intermittent contacts with the venular
endothelium and thereby moving definitely more slowly
than the freely moving leukocytes in the center line of the
microvessel. Adherent leukocytes were defined as cells attached to the
venular wall for >20 seconds. Vessel segments with a length of
100 µm were studied during an observation period of 1 minute.
Furthermore, the velocity of freely flowing leukocytes (millimeters per
second) in the central flow axis was quantified. In a given vessel
segment, the velocities of at least 30 leukocytes were measured at each
time point, and the harmonic mean h [mm/s] was calculated.
The result was used as an estimate for the blood flow velocity in
venules. Using the diameters of the venules (D) and the
velocity of the freely moving leukocytes (V), the shear rate
(seconds-1) in each single venule was calculated as
=(Vmean/D)x8.
Experimental Design
Animals (n=6) were randomly assigned to the control and the
different treatment groups with infusion of PAF at concentrations of
10-12 to 10-6 mol/L, including the group to
study the PAF antagonist. After implantation of the cranial
window and start of the superfusion with mock CSF, the animals were
allowed to stabilize during a control period of 60 minutes. During this
time 4 baseline measurements at 20 minute intervals were performed.
Before the first measurement, 2 to 3 regions of interest with at least
1 pial arteriole and 1 pial venule, respectively, were selected. Thus,
in each animal at least 2 to 3 arterioles and 2 to 3 venules were
observed and analyzed. Subsequently, PAF was infused
intra-arterially for 20 minutes. Further intravital
microscopic measurements were performed 5 minutes after the start of
PAF infusion and at the end of the infusion after 20 minutes.
The infusion of PAF or of the vehicle was followed by a 2-hour
observation period with intravital microscopic measurements at 20
minute intervals. At the end of the experiment, the integrity of the
BBB was investigated by intravenous injection of
Na+-fluorescein as barrier marker.
Data Analysis
Statistical analysis was performed with SigmaStat 1.0
software (Jandel Inc). Due to the limited number of animals in each
group, nonparametric distribution was assumed. Therefore
the Kruskal-Wallis test followed by the Mann-Whitney U test,
together with the Bonferroni-Holm procedure for repeated measurements,
were used for analyzing differences between control and treated groups.
The overall probability indicating statistical significance was set at
P<0.05. All values are reported as mean±SD.
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Results |
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Systemic Parameters
Intracranial and airway pressures remained constant in all groups throughout the experiment. The MAP transiently decreased during the infusion of PAF. Following a dose-response relationship, hypotension was most pronounced after application of the highest concentration of PAF (decreasing from 92±22 mm Hg at 0 minutes to 49±17 mm Hg at 20 minutes after PAF infusion; P<0.01; Figure 6
).
PAF also induced a dose-dependent systemic acidosis with a decrease of
blood pH and the BE, whereas the PCO2 remained
unchanged (Table). Furthermore, a slight
transient increase of the hemoglobin concentration (in milligrams per
deciliter) from 15.3±1.5 to 17.8±2.9 (NS) and of the hematocrit
(%) from 41.3±5.6 to 47.9±10.3 (Table; NS) was found 20
minutes after the start of the infusion of PAF at a concentration of
10-6 mol/L. The systemic leukocyte count increased
significantly after the infusion of PAF but returned to baseline values
at the end of the experiment (Table). PAF concentrations in
blood remained constant throughout the experiment in the control
group (baseline value, 7.0±1.8 ng/mL). Twenty minutes after start of
the infusion of PAF 10-6 mol/L, the concentration in blood
had increased from 4.0±3.0 ng/mL to 56.8±32.3 ng/mL compared with
6.8±1.7 ng/mL in the control group. The PAF concentration was found to
be decreased again at the end of the experiment (120 minutes;
17.5±15.9 ng/mL versus 10.9±2.6 ng/mL in the control group).
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Microcirculatory Parameters
Infusion of PAF led to an almost-immediate increase in the number
of rolling and adherent leukocytes in cerebral venules (Figures 1, 2, and 3).
Leukocyte-endothelium interactions were never observed
in arterioles, nor was plugging of capillaries by leukocytes. These
leukocyte-endothelium interactions elicited by PAF were
not limited to the period of infusion of the phospholipid but instead
continued to increase until the end of the experiment. The maximum of
leukocyte-endothelium interactions was observed after
infusion of PAF 10-6 mol/L, with the number of rolling and
adherent leukocytes increasing from 7.2±2.2 to 24.4±8.8 and from
1.9±0.5 to 6.9±2.2 cells/100 µm · min, respectively
(P<0.01), 100 minutes after the start of the infusion. The
same concentration also elicited a significant (P<0.05)
dilation of arterioles during the infusion of PAF (Figure 4), whereas the arteriolar
diameters remained unchanged in the control group and in the animals
exposed to the lower PAF concentrations. The dilation of arterioles
disappeared as soon as the administration of PAF was discontinued. The
venular diameters remained unchanged in all groups throughout the
experiment (data not shown).
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Except during the infusion of PAF 10-6 mol/L, leukocyte
velocity (data not shown) and shear rate in the pial venules (Figure 5) increased slightly in the control as
well as in the treated animals until to the end of the experiment,
without attaining statistical significance, however. During the
application of PAF 10-6 mol/L, the centerline velocity of
leukocytes decreased from 1.1±0.5 to 0.63±0.2 mm/s (NS) but
returned to baseline levels upon termination of the infusion. The shear
rate was reduced by 37% during the infusion (Figure 5). A
statistically significant correlation, however, between the decrease in
shear rate and the increase in the number of rolling and adherent
leukocytes was not found in any of the experimental groups. Control of
BBB integrity with Na+-fluorescein at the end
of the experiment revealed no extravasation of the fluorescence
marker in either in the control or in the PAF group.
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Pretreatment With WEB 2170BS
Administration of the PAF receptor antagonist before
infusion of PAF 10-6 mol/L inhibited the PAF-induced
hypotension (Figure 6
) as well as the
dilation of arterioles (Figure 4). Moreover, the induction of
leukocyte-endothelium interactions by PAF was markedly
inhibited. Whereas infusion of PAF 10-6 mol/L alone led to
a significant increase in the number of rolling and adherent
leukocytes, the response was attenuated by WEB 2170BS and did not
differ from the findings of the control group (Figures 1 and 2).
Systemic acidosis could only partially be prevented, while the
antagonist completely antagonized the increase in Hct, Hb,
and in the systemic leukocyte count (Table).
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Discussion |
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Systemic Effects
Increased blood levels of PAF have been found during shock under experimental and clinical conditions.9 10 Systemic application of PAF induces severe hypotension comparable to septic or anaphylactic conditions already in subnanomolar concentrations.11 In accordance with previous studies, infusion of PAF in our experiments led to a dose-dependent hypotension, which was limited to the time of infusion. After infusion of PAF into the carotid artery of rats, Kochanek et al6 observed a decrease in MAP by 43% after 15 minutes and of 37% after 60 minutes. Spinal cord blood flow was found to decrease by 15% secondary to the application of PAF in rabbits.12 The hypotensive response to PAF is attributed to a direct relaxation of arterioles, resulting in the reduction of the peripheral vascular resistance.13 In addition, PAF has negative inotropic effects on the myocardium.14 PAF-induced extravasation leading to hemoconcentration and reduction of the circulating blood volume has also been discussed.15 We also found a transient hemoconcentration after the infusion of PAF 10-6 mol/L. Furthermore, our results confirm observations16 concerning the development of a systemic acidosis and the increase of both the hemoglobin concentration and the systemic leukocyte count after PAF administration in rats.
Vessel Diameters
The effect of PAF on the vasomotor response of cerebral arterioles
is a matter of controversy. Edwards et al17 studied
parenchymal arterioles of rat brain in vitro but failed to demonstrate
any changes induced by PAF (10-12 to 10-6
mol/L), in contrast to respective observations by Uski and
Reinstrup18 with isolated feline or human pial arterioles.
Depending on the baseline vasomotor tone, PAF in high concentration
caused vasoconstriction and in low concentrations caused vasodilation.
The superfusion to the brain of newborn pigs by PAF induced
constriction of pial arterioles.19 In our study no direct
effect of PAF on arteriolar diameters could be observed. The dilation
of pial arterioles after infusion of PAF 10-6 mol/L seems
to be a compensatory mechanism to the compromised cerebrovascular
autoregulation following the hypotensive effect of PAF rather than a
direct effect of the agent on the arterioles. Therefore, our results do
not support the hypothesis of Kochanek et al,6 who
attributed the PAF-induced decrease in cerebral blood flow in their
study to vasoconstriction. With regard to the varying results, it can
be assumed that local administration of PAF may result in both
constriction as well as dilation of cerebral vessels depending on the
segment, the baseline vascular tone, and the dose administered.
Leukocyte-Endothelium Interactions
The current experiments demonstrate for the first time that
systemic administration of PAF induces
leukocyte-endothelium interactions in cerebral venules.
Although all concentrations were effective, the activation of
leukocytes was most pronounced after the infusion of PAF
10-6 mol/L. No clear dose-response relationship was found,
since leukocyte-endothelial interactions were more
pronounced after infusion with PAF 10-12 mol/L than PAF
10-9 mol/L. This finding could be related to the somewhat
lower shear rate after exposure with PAF 10-12 mol/L.
However, the existence of such a dose-related activation of
leukocyte-endothelial interactions by PAF remains
unclear. Dillon et al5 superfused the hamster cheek pouch
with PAF in concentrations from 10-11 up to
10-5 mol/L. They could observe a slight increase in the
number of rolling leukocytes in venules that was not dose dependent. In
contrast, the number of adherent leukocytes in venules increased
inversely with the PAF concentration. PAF 10-9 and
10-11 mol/L elicited the most pronounced response compared
with concentrations of PAF 10-5 and 10-7
mol/L. There was no difference between PAF 10-11 and PAF
10-9 mol/L. On the other hand, Tonnesen et
al.20 found an enhanced neutrophil adherence to cultured
human microvascular endothelial cells in a
dose-dependent manner.
Margination of leukocytes, rolling, adherence, and finally emigration into the surrounding tissue are considered to be the initial steps in the process of inflammation.21 Margination, which seems to depend on the fluid-mechanical forces, is a major factor for the induction of leukocyte-endothelial interactions. In vitro and in vivo studies22 23 24 have shown that the frequency of rolling and adherent leukocytes is influenced by the shear rate. The reduction of the shear rate in postcapillary venules increases leukocyte rolling even when adhesion receptors are blocked25 and facilitates the margination of leukocytes.22 Above a shear rate of 400 s-1, leukocyte-endothelium interactions are at a minimum because cell elements, eg, leukocytes, are forced toward the central flow axis.24 26 We did not, however, find any correlation between the shear rate and the frequency of rolling or adherent leukocytes. The maximum of leukocyte-endothelium interactions did not occur before 1 to 2 hours after the shear rate was found to be transiently decreased by the infusion of PAF 10-6 mol/L. At the end of the experiment, leukocyte-endothelium interactions continued despite high shear rates. Therefore, an increase of leukocyte-endothelium interactions secondary to fluid-mechanical factors can be excluded, which makes an enhanced expression of leukocyte adhesion receptors much more conceivable. This conclusion is further supported by the fact that the induction of leukocyte-endothelium interactions also occurred after the application of the lower concentrations of PAF, which did not lead to dramatic changes in the systemic parameters, eg, MAP, pH, and BE.
Blood-Brain Barrier
Kumar et al27 demonstrated an increased permeability
of the BBB to lactate after PAF exposure of isolated perfused rat
brains. In the present study, however, we did not observe an
increase in the permeability of the BBB at the end of the experiment.
Nevertheless, a transient opening of the BBB during the infusion of PAF
or at a later time point cannot be excluded. Because activation of
leukocytes may lead to an opening of the BBB,28 it is
conceivable that the current increase of leukocyte adherence to the
venular endothelium eventually enhances vascular
permeability at a time beyond the observation period of 2 hours in our
experiments.
Inhibition of the PAF-Induced Effects by WEB 2170BS
WEB 2170BS is a competitive receptor antagonist
that has been found to inhibit PAF effects in a variety of
studies.29 In our experiments, pretreatment with this
substance almost completely antagonized PAF-induced hypotension and the
increase in the number of circulating leukocytes, whereas the
development of the metabolic acidosis was only partially
inhibited. The antagonist also inhibited PAF-induced
rolling and adhesion of leukocytes at the venular
endothelium, which indicates that these effects can be
specifically initiated by PAF.
In summary, the present findings provide evidence that increased concentrations of PAF in the systemic circulation, besides lowering blood pressure, may lead to disturbances of the cerebral microcirculation, including activation of leukocyte-endothelium interactions. Thus, in shocklike conditions the microvascular perfusion of the brain may not only be affected by severe impairment of the macrohemodynamics but also by a PAF-specific activation of leukocyte-endothelium interactions in cerebral blood vessels, leading to margination and emigration of leukocytes as the initial steps of an inflammatory reaction. The specificity of the present findings is demonstrated by the experiments with the administration of the PAF receptor antagonist WEB 2170BS, which was blocking the PAF-related effects. It may thus be concluded that deterioration of brain function in hemorrhagic or septic shock may be at least in part attributable to the systemic release of PAF resulting in alterations of the cerebral microcirculation and induction of inflammatory reactions in cerebral microvessels.
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Acknowledgments |
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This study was supported by the Deutsche Forschungsgemeinschaft Schü 754-1/1.
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References |
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